Project Summary/Abstract In this Administrative Supplement application, we propose to apply our targeted integration strategy to build a novel in vivo zebrafish model of microglia inflammasome signaling in neuroinflammation. Chronic neuroinflammation driven by microglia activation underlies the pathophysiology of Alzheimer?s Disease (AD) and (PD) and related dementia. a-synuclein secreted by neurons in Parkinson?s patients form aggregates that are taken up by microglia, however, our understanding of the downstream intracellular mechanisms that signal microglia inflammasome activation is incomplete. We will build on our expertise in zebrafish site directed genome engineering and mouse models of neuroinflammation to generate a zebrafish model of conditional active fyn kinase that will allow temporal and spatial induction of microglia inflammasome signaling and activation. Our model will provide an in vivo platform for phenotypic chemical screens that recapitulates the cellular complexity of neuroinflammation. The new tools we develop for microglia specific Cre expression and conditional control of inflammasome signaling will provide an important resource for zebrafish researchers investigating immune function in disease pathogenesis as well as development of translational strategies.